This Phase I application requests funds to support the continued preclinical evaluation of a novel opioid analgesic, PPL-103, and the synthesis and initial preclinical evaluation of a series of new analogs thereof. PPL-103, a potent analgesic, has undergone early preclinical studies by Phoenix PharmaLabs, Inc. (PPL), the applicant organization, and NIDA. PPL-103 is the product of a cutting-edge analgesic technology being developed by PPL. It is a second-generation analog of a seminal but off-patent compound, PPL-101, discovered in 1979. Both analgesics show low addiction liability and dysphoria in animals. Thus, they represent a possible major advance in the treatment of all pain syndromes, including neuropathic pain. PPL-101 and -103 are derived from morphine and levorphanol, respectively, so they chemically resemble hundreds of old, morphine-like drugs. However, they also contain a chiral N-substituent, which confers them with unique combinations of high binding affinities and partial agonist activities at mu, delta, and kappa opioid receptors, leading to superior in vivo pharmacology compared to all conventional opioids. PPL-101 elicits potent analgesia with minimal effects on gastrointestinal transit, respiration, physical dependence, and diuresis. PPL-103, a newer analog, is an even more potent analgesic with apparently less addiction liability. Moreover, though both compounds are intrinsically non-addictive, they successfully substitute for morphine in dependent animals without precipitating withdrawal. Thus, PPL has discovered not only a new class of opioid with apparently ideal properties but also a unique receptor activity profile that confers such properties. These proposed Phase I studies aim (a) to continue evaluating the low addiction properties of PPL-103 and (b) to produce additional PPL-103 analogs containing varied chiral substitutions and to characterize them in a battery of in vitro tests and in vivo tests. Such tests will include: receptor binding, functional pharmacology, tail- flick and hot-plate analgesia, duration of action, and addiction liability [using Conditioned Place Preference (CPP) and Drug Self-Administration models]. This program will advance upon earlier discoveries and understandings gained by PPL, expand the technology pipeline, and provide new insights on a unique receptor profile, thus allowing PPL to pinpoint a desired opioid receptor profile and how it leads to non-addicting, low side-effect analgesia that is free of dysphoria. New analgesics with unique, "balanced" opioid receptor activities could permit the treatment of many pain syndromes, including neuropathic pain, with limited side effects and no physical dependence. The superior profile of such compounds could achieve improved outcomes in neuropathic pain via dose escalation, which is not possible with current opioids. PUBLIC HEALTH RELEVANCE: Opioids are still the most effective and widely used treatments for acute and chronic pain. However, the problems associated with morphine and other standard opioid analgesics are well characterized. Their use is routinely constipating, their chronic use leads to physical and psychological dependence, and their overdose leads to respiratory depression and death. This project aims to discover new analgesics with unique, "balanced" opioid receptor activities as preferred alternatives to conventional opioids. Such compounds could permit the treatment of many pain syndromes, including neuropathic pain, with limited side effects and no physical dependence. Such compounds could be positioned (a) in place of or following current opioids for treating acute and chronic back, cancer, and surgical pain, and (b) in combination with non-opioid analgesics, for treating neuropathic, acute and chronic inflammatory, and migraine pain, which are largely beyond conventional opiate regimens, due to side-effect and/or efficacy issues. The superior profile of our compounds could achieve improved outcomes in neuropathic pain via dose escalation, which is not possible with current opioids.